This R01 is a competitive renewal of a MERIT Award. When this project started (1981), the universal view was that the efficacy of ECT was dependent on the generalized seizure, while its cognitive effects were largely determined by electrical dosage. Nonetheless, standard practice involved treating all patients with the same electrical dose, typically at device maximum. Across three studies, we demonstrated marked individual differences in seizure threshold (ST). Many patients were treated orders of magnitude above ST, accounting for much of the adverse cognitive effects of ECT. We also demonstrated that the efficacy of right unilateral (RUL)ECT is highly dependent on the degree to which dosage exceeds ST. These findings have been widely replicated. In our most recent study (started and completed during the MERIT Award period), high dosage RUL ECT equaled the efficacy of a robust form of bilateral (BL) ECT, and had clinically significant advantages in acute, short-term, and long-term cognitive side effects. These findings have already had impact on practice, and should help resolve the > 40 year controversy regarding the relative merits of RUL and BL ECT. The proposed study (Study 4) began during the MERIT Award period, and this application requests support for its completion. In addition to replicating the key findings regarding the relative merits of high dosage RUL compared to BL ECT, this study takes a new direction. The traditional ECT stimulus configuration is nonphysiologic. The standard pulse width (PW) used in ECT (1-2 ms) greatly exceeds the chronaxie for the optimal stimulation necessary for neuronal depoladzation and seizure production (eg, 0.04-0.2 ms). Excessive PW results in stimulation during refractory periods long following neuronal discharge. By reducing the PW of the ECT stimulus, we should maintain efficacy, but substantially reduce cognitive side effects. Our preliminary data suggest that the magnitude of this effect equals or exceeds the difference in cognitive effects between RUL and BL ECT, and, in fact, the extraordinary difference between sine wave and brief pulse stimulation. This new study uses a randomized, double-masked, parallel group, fully factorial [RUL vs. BL ECT and ultrabrief PW (0 ms) vs. traditional PW (1.5 ms)] design, with both RUL conditions treated at 6 times initial ST and both BL conditions treated at 2.5 times initial ST. We hypothesize that high dose RUL ECT has significant advantages over moderate dose BL ECT [with both at traditional PW]. Most critically, use of an ultrabrief PW is equally effective as a long PW, but markedly reduces the short- and long-term cognitive burden of ECT, and is also superior in effects on functional status, subjective cognitive outcome, and neurophysiological alterations. Such findings should have fundamental impact on our understanding of mechanisms and on the practice of ECT.